17alpha-(1&#39;-fluoroethyl) and 17alpha-(1&#39;, 1&#39;-difluoroethyl) androstane derivatives and process therefor



3,076,325 17a-(1-FLUORQETHYL) AND 17a-(1,1'-DIFLUGRO- ETHYL) ANDRGdTANE DEREVATIVES AND PROCE$ 'I'HEREFfiR Albert Bowers and Percy George Holton, Mexico City, Mexico, assignors, by mesue assignments, to yntex Corporation, a corporation of Panama No Drawing. Filed Feb. 14, 1962, Ser. No. 173,134 12 Claims. (Cl. 260-3914) The present invention relates to novel cyelopentanophenanthrene derivatives and to a process for the production thereof.

More particularly the present invention relates to novel 17u-(l-fiuoroethyl) and 17oc-( l,l-difluoroethyl) derivatives of the androstane series.

The novel compounds of the present invention are represented by the following formulas:

(\R jonron, I

In the above formulas R represents hydrogen or methyl; R represents hydrogen or a hydrocarbon carboxylic acyl group of less than 12 carbon atoms and Z may be a double bond or a saturated linkage between C-4 and C-5.

The compounds represented by the formulas are anabolie-androgenic agents with a favorable anabolic-andro-- genie ratio. Their particular utility lies in the fact that they are devoid of liver toxicity. Additionally they are anti-estrogenic and anti-progestational compounds With anti-gonadotrophic properties. serum and liver cholesterol levels and are appetite stimulants. They are in addition useful intermediates in the production of other derivatives of high anabolic activity.

The novel 17ot-(l'-fiuoroethyl) derivatives of the present invention are prepared by the process represented by the following formula scheme:

New

?H (RH AljCH=CHz (\ljOH F CH 7 I R 6 They lower the blood,

3,fi76,825 "Patented Feb. 5, 1953 methylene chloride and tetrahydrofuran, using as catalyst boron trifluoride etherate, at a temperature lower than 10 C. for a period of time of the order of 6 hours,

thus affording the corresponding 17a-(1-fiuoroethyl) derivative (II).

The 17a-(1,1'-difluoroethyl) derivatives of the present invention are prepared by the process exemplified as III) (IV) In the above formulas R and Z have the same meaning as previously set forth.

In practicing the process just outlined the starting compound (III) .which is a member of the group consisting of l7gx-ethynyl testosterone, 17a-ethynyl dihydrotestosterone and the 19-nor derivatives thereof, is treated with hydrogen fluoride, in an inert solvent such as tetrahydrofuran in the presence of boron trifluoride etherate, at a 1 temperature under 10 C. for a period of time of the order of 6 hours, thus yielding the corresponding 17a- (1,1-difluoroethyl) derivative (IV). I

All of the compounds obtained by the above described procedures have a tertiary hydroxyl at the 17B-position and are conventionally acylated in the presence of ptoluenesulfonic acid with an acylating agent such as an anhydride derived from a hydrocarbon carboxylic acid of the previously defined type, thus giving the corresponding 17-acylates.

The following specific examples serve to illustrate, but are not intended to limit the scope of the present invention:

Example I In a polyethylene flask, adapted with magnetic stirrer, there was dissolved 2.8 g. of 17a-vinyl-testosterone in 30 cc. ofmethylene chloride, the solution was cooled to 0 C. and a solution of 12 g. of anhydrous hydrogen fluoride in 20 cc.- oftetrahydrofurane cooled in a Dry Ice acetone bath C.) was added over a period of 20 minutes with constant stirring, then there was further added 1 cc. of freshly distilled boron. trifiuoride- 'etherate. The mixture was stirred at a temperature lower than 10 C. for 6 additional hours, then neutralized.

by cautiously adding a 5% aqueous sodium bicarbonate solution and transferred to a separatory funnel. organic layer was washed with Water, dried over anhydrous sodium sulfate and concentrated until formation of an abundant precipitate. The mixture was cooled, the

The i precipitate filtered and redissolved in hotvethyl acetate,,,

the insoluble material was filtered off and the filtrate cooled whereby there crystallized l7a-(1'-fluoroethyl) testosterone. (This compound is a mixture of the optical isomers of the l-fluoroethyl group.)

3 Example IV 17u=ethinyl-dihydrotestosterone was fiuorin'ated by the procedure described in Example I, thus furnishing 17a- (l',l-difluoroethyl) dihydrotestosterone.

Example V l7z=vinyl 1'9-nor-test0sterone was treated according to Example I" to give 1'7b(l' fluoroethyl)-19-nor-testosterone.

Ex'am'pleVl Upon reaction of l7a-ethinyl-19-nor-testeronewith hydrogen fluoride, following the procedure of Example I, there was obtained l7a-(l,l'-difluoroethyl)-19-nor testosterone.

Example V11 hours afroomtemperature, poured-into ice and water,

and tlie resultingnriixture stirred'to effect Hydrolysis of theexce'ssanhydride. Theben'z'ene layer was separated and washed with sodium" carbonate solution and water; D'rying',fle aporation and crystallization ofthe residue fr m" ether-hexane produced' a mixture ofthe acetate of"172zf(lfluoroethyl)testosterone and the enol acetate thereof. This'niixture was treated with 10000. of""cbld2% methanolic" potassium hydroxide. The re action mixture was"kept'at0' C. for'one hour and then poured into water and neutralized-with dilute" hydro ch'lrBrid-a'eid'. Ether extraction and crystallization of the residue yielded ure acetate of" 17014 l'-fluoroethyl)- testosterone.

When applying the above" technique to the starting compounds under. 1 there were obtained the cor-responding; products. 115

, ethyl)-19-n0r-dihydrotestosten one.

example, were treated by the procedure described in said example, with the exception that acetic anhydride was substituted by propionic anhydride, caproic anhydride and cyclopentyl propionic anhydride thus affording respectively the propionates, caproates and cyclopentylpropionates of the said compounds.

We claim:

1. A compound of the following formula:

wherein R is a member of the group consisting of hydrogen=and-methyl; R isselected from the group consisting of hydrogen and a hydrocarbon-carboxylic acyl group of less than 12 carbon atoms; and Z is a member of the group consisting of asaturated linkage and a double bond between G l-"and G-i.

2. 17 0L-( l-fluoroethyl) -testosterone.

3. 17a-(1-fiuoroethy1)-dihydrotestosterone.

4. 17 a-( 1'-fluoroethyl') 1 9 nor-testosterone.

5. 17oc-( l-fiuoroethyl) -l9-11or-dihydrotestosterone.

6. A compound of the following formula:

l i' --o F2013;

wherein R is a member of the group-consisting of hydrogen and methyl;.R is selected from the group consisting of hydrogen and a' hydrocarbon carboxylic acyl group of less than carbon atoms and Z is-a member-offthe" pound withhydrogen fluoride in an" inert solventand in theresence ofb'or'on'trifiuor-ide 'eth'erate:

ethyl -androstan- 1 -01 derivatives which comprises treating the corresponding 17a-ethynyl-androstan-17(3-01compound wlth-hydrogen fluoride m an inert solvent and in theprcscnce olhorontrifluoridcethn'ate. 

1. A COMPOUND OF THE FOLLOWING FORMULA: 